Acute and Subchronic Inhalation Studies on Trifluoroiodomethane Vapor in Fischer 344 Rats

Trifluoroiodomethane (CF₃I) is being considered as a replacementcompound for halon fire suppressants. Its structure is similarto that of Halon 1301 (CF₃Br), but it has very low ozone depletionpotential compared to CF₃Br. As part of the process of developingenvironmental and health effects criteria, acute, 2-week, and13- week nose-only inhalation toxicity studies were conductedin Fischer 344 rats. In the acute study, three groups of 30male rats each were exposed to 0 (control), 0.5, or 1.0% (v/v)CF₃I for 4 hr and euthanized immediately following exposure,3 days postexposure, or 14 days postexposure. There were nodeaths and no clinical signs of toxicity throughout the study.Histopathologic examination of select tissues showed no lesionsof pathologic significance. In the 2-week study, four groupsof 5 male rats each were exposed for 2 hr/day, 5 days/week to0, 3, 6, or 12% CF₃I No deaths were observed, though lethargyand slight incoordination were noted in rats of the 6 and 12%groups at the conclusion of each daily exposure. Mean body weightgains were depressed in rats of the 6 and 12% groups. Serumthyroglobulin and reverse T₃ (rT₃) values were increased atall exposure levels. At necropsy, no gross lesions or differencesin absolute or relative organ weights were noted. Histopathologicexamination of the thyroid and parathyroid glands indicatedno morphological abnormalities in the CF₃I-exposed rats. Inthe 13-week study, four groups of 15 male and 15 female ratswere exposed to 0, 2, 4, or 8% CF₃I 2 hr/day, 5 days/week for13 weeks. Rats exposed to 4 or 8% CF₃I had lower mean body weightsthan the controls. Deaths observed in the 2 and 8% groups wereattributed to accidents resulting from the restraint systememployed. Hematologic alterations were minimal and consideredinsignificant. Increases in the frequency of micronucleatedbone marrow polychromatic erythrocytes were observed in ratsof all three CF₃I groups. Serum chemistry alterations observedin rats of all CF₃I exposure groups included decreases in T₃and increases in thyroglobulin, rT₃, T₄, and TSH. Relative organweight increases (8% CF₃I group) occurred in the brain, liver,and thyroid glands; decreases were observed in the thymus andtestes. A decrease in relative thymus weights and an increasein relative thyroid weights were observed also in rats of the2 and 4% groups. Histopathological findings included a mildinflammation in the nasal turbinates of rats exposed to 4 or8% CF₃I, mild atrophy and degeneration of the testes (4 and8% CF₃I groups), and a mild increase in thyroid follicular colloidcontent in rats of all CF₃I exposure groups. Though NOAELs wereobserved for select target organs (e.g., nasal turbinates, testes),NOAELs were not apparent in all target organs examined (e.g.,thyroid glands, bone marrow).     

Acute, Subchronic, and Chronic Toxicity of the Cardiotonic Isomazole in Rats

Acute, subchronic, and chronic toxicity studies were conductedwith isomazole, a new (investigational) inotropic agent withsignificant vasodilator properties. When given acutely to eitheryoung adult rats or mice, the oral median lethal dose was approximately135 or 525 mg/kg, respectively. Clinical signs of toxicity wereleg weakness, hypoactivity, tremors, clonic convulsions, andataxia. Fischer 344 rats (15/sex/group) were fed diets containingisomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 monthswith no resulting mortality or clinical signs of toxicity. Theaverage daily intake of the compound was approximately 0, 20,65, or 198 mg/kg in both sexes. Body weight gain, food consumption,and efficiency of food utilization were significantly reducedonly in males in the 198 mg/kg dose group. There were no changesof toxicological significance in any of the hematology, clinicalchemistry, or urine parameters. Isomazole produced significantincreases in hepatic p-nitroanisole O-demethylase activity andrelative liver weight primarily at the 65 and 198 mg/kg treatmentlevels. These effects were consistent with induction of thehepatic drug-metabolizing enzyme system. Histopathologic findingsconsisted of centrilobular fat deposition in the livers of 9of 15 males in the 198 mg/kg dose group, and periarteritis inthe adventitia of small and medium-sized arteries in the mesenteryin 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dosegroups, respectively. The plasma levels of isomazole had a tendencyto drop after 90 days compared to Day 2 in all dose groups andwas more apparent in male rats. There was no accumulation ofeither isomazole or the two metabolites in the serum over the3-month period. The average daily intake of isomazole was 0,12, 30, or 76 mg/kg/day in the 6-month rat study(l0 animals/sex/group)and 0, 10, 26, or 68 mg/kg/day in the 1-year rat study (20 animals/sex/group).Qualitatively, no findings occurred in the 6-month and 1-yearstudy which differed from those in the 3-month study.     

Subchronic Inhalation Studies of Styrene in CD Rats and CD-1 Mice

Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived)rats were exposed to styrene vapor at 0, 200, 500, 1000, or1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrenehad no effect on survival, hematology, or clinical chemistry.Males at 1500 ppm weighed 10% less after 13 weeks and malesand females at 1000 and 1500 ppm consumed more water than controls.Histopathologic changes were confined to the olfactory epitheliumof the nasal mucosa. Groups of 20 male and 20 female CRL CD-1and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60,250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortalitywas observed in both CD-1 and B6C3F1 mice exposed to 250 or500 ppm; more female mice, but not males, died from exposureto 250 ppm than from 500 ppm. Groups of 10 male and 10 femaleCRL CD-1 mice were exposed to styrene vapors at 0, 50, 100,150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Twofemales exposed to 200 ppm died during the first week. Livertoxicity was evident in the decedents and in some female survivorsat 200 ppm. Changes were observed in the lungs of mice exposedto 100, 150, or 200 ppm and in the nasal passages of all treatmentgroups, those exposed to 50 ppm being less affected. Satellitegroups of 15 male rats and 30 male mice were exposed as describedabove for 2, 5, or 13 weeks for measurement of cell proliferation(BrdU labeling). No increase in cell proliferation was foundin liver of rats or mice or in cells of the bronchiolar or alveolarregion of the lung of rats. No increase in labeling index oftype II pneumocytes was seen in mouse lungs, while at 150 and200 ppm, an increased labeling index of Clara cells was seenafter 2 weeks and in occasional mice after 5 weeks. Large variationsin the labeling index among animals emphasize the need for largegroup sizes. For nasal tract effects, a NOAEL was not foundin CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For othereffects, the NOAEL was 500 ppm in rats and 50 ppm in mice.     

Methyl Isocyanate Subchronic Vapor Inhalation Studies with Fischer 344 Rats

Methyl Isocyanate Subchronic Vapor Inhalation Studies with Fischer344 Rats. DODD, D.E., AND FOWLER, E.H. (1986). Fundam. Appl.Toxicol. 7, 502-522. Groups of Fischer 344 rats were exposedto 3.1, 0.6, 0.15, or 0.0 (control) ppm of methyl isocyanate(MIC) vapor 6 hr per day for two 4-day sessions separated bya 2-day rest. There were no deaths during the study. The ratswere killed the morning following the last exposure day. The3.1 -ppm-exposed rats had decreased body weight, food consumption,and blood oxygen saturation (males only). Increased hemoglobinconcentration (males only) and lung weights were also observedin this group of rats. Multiple histologic lesions, limitedto the respiratory tract, were observed in rats of the 3.1-ppmgroup only. The lesions consisted of necrosis, suppurative inflammation,squamous metaplasia, and intraluminal and submucosal fibroplasia(bronchi and bronchioles only) which extended from the anteriornasal cavity to the terminal bronchioles. In a second study,rats were exposed to 3.0 ppm MIC, 6 hr per day, for either oneor two 4-day sessions and sacrificed on postexposure Days 1,15,43,and 85. All rats survived the 4- or 8-day exposure regimen,although significant decreases in body weight and encrustationof the eyes, nose, or mouth area were observed. During the first15 days postexposure, male mortality was 63%; only 6% of theMIC-exposed females died. The cause of death was interpretedto be a combination of pulmonary vascular and inflammatory changescoupled with anorexia. For survivors, recovery from the necrotizingand irritating effects of MIC vapor was observed. Squamous metaplasiaof respiratory epithelium, observed in rats sacrificed at theend of the exposure period, was replaced by tall pseudostratifiedcolumnar (regenerative) epithelium beginning in the bronchiand bronchioles as well as the distal trachea. Collagen maturationand condensation of the intraluminal and submucosal fibroplasiaoccurred during the postexposure period. The results of theseinvestigations support the current threshold limit value forMIC of 0.02 ppm.     

Subchronic Inhalation Toxicity of Tetramethoxysilane in Rats

Sprague-Dawley rats were exposed 6 hr/day, 5 days a week, for28 days to tetramethoxysilane (TMOS) at concentrations of 0,1, 5, and 10 ppm (Phase I study) and to 0, 15, 30, and 45 ppm(Phase II study). All of the rats exposed to 45 ppm TMOS diedor were sacrificed in a moribund state during the 28-day studyperiod. Statistically significant changes were observed in foodconsumption, body weights, and clinical chemistry parametersin the animals exposed to 30 ppm TMOS. Males exposed to 15 ppmTMOS showed a significant decrease in total protein. No effectswere seen in rats exposed to 1, 5, and 10 ppm TMOS. Histopathologicallesions related to TMOS exposure were observed in the respiratorytract tissues and eyes of rats exposed to 15, 30, and 45 ppmTMOS. The principal types of lesions observed were ulceration,inflammation, and necrosis of epithelium. At 45 ppm, changesat these sites were severe and present in all animals. Changesat 30 ppm, while occurring in all rats, were much less severethan those seen at 45 ppm. At 15 ppm, the changes were minimaland occurred only in three males and five females. The dataof this study showed that TMOS has a steep dose-response curvewith no observable effects at 10 ppm, very minimal effects at15 ppm, moderate to severe effects at 30 ppm, and severe effectsand lethality at 45 ppm.     

Subchronic Inhalation Toxicity of Hexamethylenediamine in Rats

Four groups of 15 male and 15 female Sprague-Dawley-derived(CD) rats each were exposed to aqueous hexamethylenediamine(HMD) aerosols for 6 hr/thy, 5 days/week for 13 weeks at meananalytical concentrations of 0, 12.8, or 51 mg/m³ Because ofexposure-related deaths in a group of male and female rats similarlyexposed to 215 mg/m³ HMD, this group was terminated during theseventh week of the study. Signs of respiratory and conjunctivalirritation were observed in rats at both the 51 and 215 mg/m³HMD test levels. Body weight gain was significantly reducedin both sexes exposed to 215 mg/m³ HMD. At the 5-week studyinterval, slight hemopoietic stimulation of peripheral bloodparameters was observed in rats of both sexes exposed to 215mg/m³ HMD. Treatment-related microscopic lesions were seen onlyin rats exposed to 215 mg/m³ MD and were confined to the trachea,nasal passages, and lungs. The noeffect level in this studyis considered to be 12.8 mg/m³ HMD.     

Subchronic Inhalation Study of Toner in Rats

Abstract

A subchronic inhalation study of a special test toner was conducted by exposure of groups of F-344 SPF (specific pathogen free) rats for 6 hlday, 5 dayslwk for 13 wk. The test material was a special 9000 type xerographic toner, enriched in respirable size particles compared to commercial toner, such that it was about 35% respirable according to the ACGIH criteria. The nominal aerosol exposure concentrations were 0, 7.0, 4.0, 76.0, and 64.0 mg/m³ Body weight, clinical chemistry values, food consumption, and organ weights were normal except for a 40% increase in lung weight for the highest exposure group. Histopathological examination of the lungs indicated an exposure-related accumulation of particle-laden alveolar macrophages. A very slight degree of septal thickening of the alveolar structure was noted in the highest exposure group. Clearance results for the test material and a superimposed spike of ⁵⁹Fe₂O₃ were essentially unchanged at exposure concentrations of 0, 1, and 4 mg/m³. At 76 mg/m³, some indications of retarded clearance were noted and at 64 mg/m³, no appreciable toner clearance was observed. The pulmonary changes observed at the two highest exposure levels are interpreted on the basis of the “lung overloading” concept. Based upon the above observations, as well as the increase in lung weight, both the maximum tolerated dose (MTD) and the maximum functionally tolerated dose of test toner (MFTD) in this subchronic study were exceeded at the 64 mg/m³ exposure level.     

Acute, Subacute, and Subchronic Inhalation Toxicity Studies of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats

Short-term inhalation toxicity studies with respirable polymericmethylene diphenyl diisocyanate (polymeric MDI) aerosol wereperformed in rats. The 4-hr LC50 was found to be 490 mg polymericMDI/m³ (95.5% <4.3 µm). Exposure of (4-week-old) ratsto 0, 2.2, 4.9, or 13.6 mg polymeric MDI/m³ (95% < 5 µm)for 2 weeks resulted in mortality, severe growth retardation,and elevated lung weights at 13.6 mg/m³ at 4.9 mg/m³ slightgrowth retardation and slightly elevated lung weights were observed.A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or7.2 mg polymeric MDI/m³ (95% < 5 µm) revealed transientgrowth retardation and a slightly increased number of pulmonaryalveolar macrophages occasionally accompanied by increased numbersof mononuclear cells and fibroblasts in alveolar septa onlyat 7.2 mg/ m³ In a second 2-week study with 4 or 6-week-oldrats exposed to 14.1 mg polymeric MDI/m³ (95% < 5 µm),4-week-old rats died earlier and in greater numbers than 6-week-oldrats. In a second 13-week study with 6-week-old rats, usingexposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymericMDI/ m³ (95% < 5 µm) and including a 4-week recoveryperiod, 12.3 mg/ m³ induced mortality, growth retardation, severerespiratory distress, increased lung weights, degeneration andhyperplasia of the nasal epithelium, accumulations of macrophagesin the lungs and mediastinal lymph nodes, and focal inflammatorychanges in the lungs. Rats exposed to 8.4 mg/ m³ showed respiratorydistress, lower body weights in males, increased lung weights,and similar, but much less severe, histopathological changesin the respiratory tract and mediastinal lymph nodes. Most ofthe histopathological changes seen at the higher concentrationswere also seen at 4.1 mg/m³ but to a very minor degree and ina few rats only. At the end of the 4-week posttreatment periodthe microscopical changes in nose, lungs, and mediastinal lymphnodes were still present but generally to a much less degreethan at the end of the exposure period. It was concluded thatthe dose-effect curve for repeated exposures of rats to respirablepolymeric MDI is very steep, and that the "no-observed-adverse-effectlevel" of polymeric MDI was 1.4 mg/m³ the actual no-adverse-effectlevel being lower than but most probably very close to 4.1 mg/m³.     

吸入流行性出血热病毒气溶胶在大白鼠体内的沉积、转运观察

实验大鼠吸入用荧光素标记 EHFV 制备的 EHFV 气溶胶后,观察其体内清除、转运规律。结果发现,最初主要转运途径是经血液吸收和巨噬细胞吞噬,继而分布到各脏器,亦可通过肾脏随尿排出体外。整个清除转运过程约10天左右。     

Subchronic Inhalation Toxicity of Ethylbenzene in Mice, Rats, and Rabbits

Mice, rats, and rabbits (five/sex/group) were exposed by inhalationto ethylbenzene (EB) vapors for 6 hr/day, 5 days/week for 4weeks (20 exposures). Rats and mice received 0, 99, 382, or782 ppm EB while rabbits received 0, 382, 782, or 1610 ppm.No changes were evident in mortality patterns, clinical chemistries,urinalyses, or treatment-related gross/microscopic (includingophthalmologic) lesions. Rats exhibited sporadic lacrimationand salivation, as well as significantly increased liver weightsat 382 and 782 ppm, and small increases in leukocyte countsat 782 ppm. Males at this exposure level also showed marginalelevations in platelet counts. In mice, females showed statisticallyincreased absolute and relative liver weights at 382 and 782ppm, while males had statistically increased relative liver-to-brainweight ratios only at 782 ppm. Female rabbits at the high exposurelevel of 1610 ppm gained weight more slowly than controls (notstatistically significant); males showed a similar transientdownward trend after 1 week, but showed no differences fromcontrols at study's end. A no observed adverse effect level(NOAEL) of 382 ppm appears appropriate for rats and mice witha lowest observed adverse effect level (LOAEL) of 782 ppm. ANOAEL of 782 ppm and LOAEL of 1610 ppm are appropriate for rabbits.     

Subchronic Inhalation Toxicity of 1,1,1,3-Tetrachloropropane in Rats

The purpose of this study was to evaluate the inhalation toxicityof 1,1,1,3-tetrachloropropane (TCP), an intermediate in productionof chlorinated silicone fluids. Male and female Sprague- Dawleyrats were exposed 6 hr/day, 5 days/week, for days to TCP atconcentrations of 0, 25, 75, or 225 ppm (Phase study) and to0, 1, 5, or 10 ppm (Phase II study). Phase II of study was conductedbecause a no-observed-effect level was not achieved in PhaseI. No animals died during the study. Clinical signs of toxicityincluded oral, nasal, and/or ocular discharge. No statisticallysignificant differences were observed in either body weightsor food consumption between exposed and control animals. Clinicalpathology did not indicate any treatment related effects. Absoluteand relative liver and kidney weights were increased in maleand female rats exposed to 225 ppm TCP, and heart weights wereincreased in male rats exposed to 225 ppm TCP. The liver andheart weight changes were supported by the findings of microscopiclesions in these organs. These lesions consisted of multifocal/focalmyofiber degeneration necrosis with adjacent chronic myocarditisin the heart and multifocal single-cell necrosis in the liverparenchyma. The liver lesions had essentially resolved at theend of a 28-day recovery period but the heart lesions were stillpresent in male rats in the recovery group exposed to 225 ppmTCP. No treatment-related effects were observed in animals exposedto 1, 5, or 10 ppm TCP. The data of this study showed that theno-observable-effect level for TCP was 10 ppm in male and femaleCD rats.     

Subchronic Inhalation Toxicity of Dimethylformamide in Rats and Mice

ABSTRACT

Fisher F344 rats and B6C3F1 mice were exposed to concentrations of 0, 150, 300, 600 and 1200 ppm of dimethylformamide (DMF) for 6 hours a day, 5 days a week for 12 weeks. Detailed clinical observations were obtained weekly and body weights biweekly on all animals. Clinical chemistry and hematology evaluations were made on all rats and approximately half the mice at terminal sacrifice. Gross necropsy examinations were made on all animals. Histopathologic evaluations were conducted on selected tissues of animals of both species at all dose levels. Few overt signs of toxicity were seen in either rats or mice. There was a dose related depression in body weight gain in rats that was significant at the 1200 ppm level from the second week of study onwards. A total of 11 mice died or were sacrificed moribund during the study, 8 from the high dose and 2 from the 600 ppm dose level. Both clinical chemistry (in rats only) and gross necropsy observations, and histopathology of tissues indicate the possibility that liver may be the target in specific organ toxicity. The no-effect DMF dose was below the 150 ppm level for both rats and mice and the maximum tolerated dose was below the 600 ppm level.     

Oral Toxicity of Carbon Tetrachioride: Acute, Subacute, and Subchronic Studies in Rats

Oral Toxicity of Carbon Tetrachloide: Acute, Subacute, and SubchronicStudies in Rats. BRUCKNER, J. V., MACKENZIE, W. F., MURALIDHARA,S., LUTHRA, R., KYLE, G. M., AND ACOSTA, D. (1986). Fundam.Appl. Toxicol. 6, 16–34. This investigation was conductedto characterize the acute, subacute, and subchronic toxic potencyof ingested carbon tetrachloride (CCl₄) In the first acute andsubacute toxicity study, male Sprague-Dawley rats of 300–350g were gavaged with 0, 20, 40, or 80 mg CCl₄/kg once daily for5 consecutive days, rested for 2 days, and dosed once dailyfor 4 additional days. Rats of 200–250 g were gavagedwith 0, 20, 80, or 160 mg CCl₄/kg according to the same dosageregimen in the second acute and subacute study. In the firstand second studies one group of rats at each dosage level wassacrificed for clinical chemistry and histopathological evaluationat 24 hr, 4 days, and 11 days after initiation of dosing. Single20- and 40-mg/kg doses had no apparent toxic effect at 24 hr,although 80 mg/kg caused mild hepatic centrilobular vacuolizationand significant increases in some serum enzyme levels. In general,there was progressively severe hepatic injury at each dosagelevel over the 11-day period. CCl₄ was more hepatotoxic to the200–250-g rats than to the 300–350-g rats. In thesubchronic study, rats initially 200–250 g were gavaged5 times weekly for 12 weeks with 0, 1, 10, or 33 mg CCl4/kgBody weight and clinical chemistry indices were monitored duringthe 12 weeks of dosing and 2 weeks after cessation of dosing,A dose of 1 mg/kg had no apparent adverse effect; 10 mg/kg producedslight, but statistically significant increases in sorbitoldehydrogenase activity and mild hepatic centrilobular vacuolization;33 mg/kg caused marked hepatotoxicity. Serum enzyme levels remainedelevated during the 12-week dosing period, but returned towardnormal within 13 days of cessation of CCl₄ exposure. Microscopicexamination of livers of the 33-mg/kg rats revealed cirrhosis,characterized by bile duct proliferation, fibrosis, lobulardistortion, parenchymal regeneration, hyperplastic nodules,and single-cell necrosis. The fibrosis was not reversed withinthe 13-day recovery period.     

Subchronic Inhalation Toxicity of Methyl Isoamyl Ketone in Rats

Subchronic Inhalation Toxicity of Methyl Isoamyl Ketone in Rats.KATZ, G. V., RENNER, E. R., JR., AND TERHAAR, C. J. (1986).Fundam. Appl. Toxicol. 6, 498–505. Rats were exposed byinhalation, 6 hr/day, 5 days/week, to target vapor concentrationsof 2000, 1000, or 0 ppm of methyl isoamyl ketone (MIAK) for12 exposures spanning 16 days, and 2000, 1000, 200, or 0 ppmfor 69 exposures spanning 96 days. Body weights, hematology,and serum clinical chemistry determinations were comparableto controls in both inhalation studies. Clinical signs of toxicitywere lethargy and decreased aural response (2000 ppm, 2-weekstudy; 2000 and 1000 ppm, 90-day study) and nasal and eye irritation(2000 and 1000 ppm, 90-day study). In addition, the excretionof gel-like casts in seminal fluid was seen in males exposedto 2000 and 1000 ppm in both studies. increases in absoluteand relative liver and kidney weights were observed in bothsexes following exposure to 2000 and 1000 ppm in the 2-weekand 90-day studies. Liver weight increases were exposure dependentand in the 90-day study reflected hepatocyte hypertrophy observedon microscopic examination. Microscopic kidney changes werehyalin degeneration or hyalin droplet formation in males inthe 2-week (2000 and 1000 ppm) and 90-day (2000 ppm) studies;and minor to moderate regeneration of tubular epithelium (2000and 1000 ppm) in both studies. Minor tubular epithelium regenerationwas seen in females exposed to 2000 ppm for 90 days. The toxicityof MIAK following inhalation exposure was not as extensive orsevere as that resulting from a prior study in which male ratswere dosed orally with 2000 mg/kg/day (a dose comparable to2000 ppm) for 13 weeks. The 90-day inhalation exposure no-observed-effectlevel for toxicity was 200 ppm MIAK.     

Subchronic Inhalation and Oral Toxicity of Hydrogenated Terphenyls in Rats

The subchronic toxicity of a commercial blend of partially hydrogenatedterphenyl was evaluated in rats by inhalation and oral routesof exposure. Animals were exposed to target concentrations of0, 10, 100, or 500 mg/m³ for 6 hr/day, 5 days/week or were offereddiets daily with concentrations of 0, 50, 200, or 2000 ppm.Each study lasted approximately 14 weeks. The study designsincluded observations for clinical signs, body weights, ophthalmicexams, hematology and clinical chemistry, major organ weights,and gross and histopathology. No treatment-related effects werenoted in the ophthalmic exams. Body weights were slightly depressedin high-dose males from the inhalation study and high-dose femalesin the dietary study. Liver and liver/body weights were increasedin high-dose animals of both sexes and high-and mid-dose malesin the dietary and inhalation studies, respectively. In thehigh-dose females of the dietary study, kidney and kidney/bodyweights were increased with increased adrenal and adrenal/bodyweights were also observed. No compound-related gross lesionsnor pathological correlates to the organ weight changes wereobserved in either study. The no-adverse effect levels wereconsidered to be 100 mg/m³ and 200 ppm (15.9 mg/kg) for theinhalation and dietary studies, respectively. These data indicatethat a wide margin of safety exists for hydrogenated terphenylworkplace exposure.     

Evaluation of Subchronic Inhalation Toxicity of Dimethyl Disulfide in Rats

This study was carried out to investigate the potential subchronic inhalation toxicity of dimethyl disulfide (DMDS) via whole-body exposure in F344 rats. Groups of 10 rats of each sex were exposed to DMDS vapor by whole-body exposure at concentrations of 0, 5, 25, or 125 ppm for 6 h/day, 5 days/wk for 13 wk. All the rats were sacrificed at the end of treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were examined. At 25 ppm, a decrease in the body weight gain, food intake, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) was observed in the males, but not in the females. However, at 125 ppm, a decrease in the body weight gain, food intake, and thymus weight and an increase in the weights of adrenal glands were observed in both genders. Serum biochemical investigations revealed a decrease in the AST, ALT, BUN, creatine phosphokinase (CPK), and triglyceride levels and an increase in the glucose level. In contrast, no treatment-related effects were observed in the 5 ppm group. The toxic potency of DMDS was slightly higher in males than that in females. In these experimental conditions, the target organ was not determined in rats. The no-observed-adverse-effect concentration (NOAEC) was found to be 5 ppm, 6 h/day for male rats and 25 ppm, 6 h/day for female rats.     

Subchronic Inhalation Study of 1-Hexene in Fischer 344 Rats

ABSTRACT

The objective of this study was to evaluate the toxicity of 1-hexene following repeated inhalation exposures in male and female Fischer 344 rats. Groups of 40 male and 40 female rats were exposed for 6 hours per day, 5 days per week, over a 13-week period. Treatment groups consisted of air-exposed control (0 ppm) and three test groups of 300, 1000, and 3000 ppm 1-hexene. During the treatment period, the rats were observed daily for clinical signs of toxicity; body weights and neuromuscular coordination [females only] were measured at 7-day intervals. After 7 weeks of exposure and at the end of the treatment period, the rats were subject to macroscopic and microscopic pathology, clinical chemistry, hematology, urinalysis, and sperm counts. No mortalities were observed during the course of the study. No clinical signs of toxicity attributable to 1-hexene exposure were observed. Female rats exposed to 3000 ppm had significantly lower body weights compared to control rats from exposure day 5 persisting throughout the treatment period. Male rats exposed to 3000 ppm had slightly but not statistically significant lower body weights in comparison to controls. Male rats exhibited slightly increased absolute and relative testicular weights, and female rats had slightly decreased absolute [but not relative] liver and kidney weights, at 3000 ppm. There were no gross or microscopic morphological findings attributed to treatment. Exposure to 1-hexene did not affect neuromuscular coordination in females as determined using the Rotarod®, nor sperm counts in male rats. Several statistically significant effects in hematology, clinical chemistry, and urinalysis evaluations were observed, but were either of small magnitude or did not correlate with histopathological findings, and thus did not appear to be of biological significance. In summary, the no-adverse-effect-level for this study was determined to be 1000 ppm, based on decreased weight gain in female rats, and on slight organ weight changes in both sexes at 3000 ppm.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(862–3125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level.